PROJECT SUMMARY/ABSTRACT Dr. Anne Drewry is an intensivist with the long-term goal of becoming an independently funded clinical trialist in the field of critical care, with a focus on the role of body temperature in sepsis. Afebrile septic patients are twice as likely to die than febrile patients, even after accounting for potentially confounding factors (e.g. age, illness severity). Given the role of inflammation and immunity in the physiology of fever generation, immune dysfunction is a potential link between failure to mount a fever and worse clinical outcomes. The objective of this proposal is to determine whether immunological phenotypes differ between febrile and afebrile patients. The central hypoth- esis is that septic patients who fail to mount a fever will demonstrate more severe sepsis-induced immune im- pairment than febrile patients. This hypothesis is supported by the candidate?s preliminary data suggesting that absence of fever is associated with impaired monocyte function and persistent lymphopenia, key mechanisms of sepsis-induced immunosuppression. It will be tested by performing a prospective cohort study with the follow- ing specific aims: (1) to determine whether febrile and afebrile septic patients exhibit differences in biomarkers of sepsis-induced immunosuppression; and (2) to compare clinical signs of immunosuppression among febrile and afebrile patients. Following enrollment, critically ill patients with severe sepsis will be divided into febrile and afebrile groups based on the presence or absence of body temperature ? 38.0C within 24 hours of sepsis diagnosis. Sepsis-induced immunosuppression will be assessed via serial measurements of monocyte HLA-DR expression, LPS-induced TNF-? production, anti-CD3/anti-CD28-induced IFN-? production, and absolute lym- phocyte counts. Clinical outcomes will include acquisition of secondary infections and reactivation of latent vi- ruses. This work is significant because it is the first step in a continuum of research that is expected to lead to targeted treatment of immune dysfunction in afebrile septic patients. The applicant will implement this project with support from of her mentors (Drs. Richard Hotchkiss and Marin Kollef) and a multidisciplinary team of advi- sors with expertise in sepsis immunology, clinical study design/execution, and statistics. The applicant, in con- sultation with her mentors, has also designed a comprehensive career development plan emphasizing training in the areas of (1) translational laboratory techniques, (2) adaptive trial design, (3) advanced statistics, and (4) planning and execution of multicenter trials, with the goal of R01 submission prior the end of the K23 award period. Given its high volume of critically ill patients and ample opportunities for research training and multidis- ciplinary collaboration, Washington University is an ideal environment to support this research project and the candidate?s overall career development.